tbuckley/cabot-search huggingface dataset:
Abstract 6398: Targeting ENPP1 to boost anti-tumor immunity during PARP inhibition
Authors: Jie Li, Charlotte Mason, Kay Hanggi, Vincent Luca, Brian Ruffell
Journal: Cancer Research (2023)

Abstract Homologous recombination (HR) deficiency confers sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPi), which have been approved for use in ovarian and triple negative breast cancers (TNBC) carrying loss-of-function mutations in HR pathway genes, most commonly BRCA1/2. Preclinical studies in BRCA1-deficient tumor models have demonstrated that the immune compartment is required for PARPi efficacy through the ability of PARPi to cause micronuclei formation and activate cGAS in tumors cells. The production of the 2’3’-cGAMP secondary intermediate stimulates STING in neighboring tumor-infiltrating immune cells to promote an anti-tumor response. Despite this evidence of immune stimulation, PARPi does not extend overall survival in TNBC patients, suggesting that immune suppression remains a significant barrier for efficacy. Here we sought to evaluate the role of ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1), a type II transmembrane glycoprotein that hydrolyzes extracellular 2’3’-cGAMP. We generated Brca1/Pten/Trp53-deficient TNBC cell lines from a genetically engineered mouse model and found that these expressed higher levels of ENPP1 than Brca1-proficient TNBC and non-TNBC cell lines. Knocking out Enpp1 via CRISPR/Cas9 increased 2’3’-cGAMP production during Niraparib treatment but did not affect cellular proliferation in vitro. Critically, knocking out Enpp1 significantly reduced the growth of orthotopic Brca1-deficient tumors, with no change in growth observed for orthotopic E0771 or PyMT models, suggesting an important role for ENPP1 in HR-deficient tumors. Therapeutic dosing of Niraparib further reduced the growth of Enpp1 knockout tumors in a manner that was dependent upon host STING and correlated with higher CD8+ T cell infiltration and effector function. These findings demonstrate that ENPP1 suppresses anti-tumor immunity in Brca1-deficient tumors, suggesting that blocking the enzymatic activity of ENPP1 may provide therapeutic benefits during PARPi treatment for TNBC patients. Citation Format: Jie Li, Charlotte Mason, Kay Hanggi, Vincent Luca, Brian Ruffell. Targeting ENPP1 to boost anti-tumor immunity during PARP inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6398.
Design and Control for WLR-3P: A Hydraulic Wheel-Legged Robot
Authors: Xu Li, Haoyang Yu, Haibo Feng, Songyuan Zhang, Yili Fu
Journal: Cyborg and Bionic Systems (2023)

The robot used for disaster rescue or field exploration requires the ability of fast moving on flat road and adaptability on complex terrain. The hybrid wheel-legged robot (WLR-3P, prototype of the third-generation hydraulic wheel-legged robot) has the characteristics of fast and efficient mobility on flat surfaces and high environmental adaptability on rough terrains. In this paper, 3 design requirements are proposed to improve the mobility and environmental adaptability of the robot. To meet these 3 requirements, 2 design principles for each requirement are put forward. First, for light weight and low inertia with high stiffness, 3-dimensional printing technology and lightweight material are adopted. Second, the integrated hydraulically driven unit is used for high power density and fast response actuation. Third, the micro-hydraulic power unit achieves power autonomy, adopting the hoseless design to strengthen the reliability of the hydraulic system. What is more, the control system including hierarchical distributed electrical system and control strategy is presented. The mobility and adaptability of WLR-3P are demonstrated with a series of experiments. Finally, the robot can achieve a speed of 13.6 km/h and a jumping height of 0.2 m.
<i>Helicobacter pylori</i>promotes colorectal carcinogenesis by deregulating intestinal immunity and inducing a mucus-degrading microbiota signature
Authors: Anna Ralser, Alisa Dietl, Sebastian Jarosch, Veronika Engelsberger, Andreas Wanisch, Klaus Peter Janssen, Moritz Middelhoff, Michael Vieth, Michael Quante, Dirk Haller, Dirk H Busch, Li Deng, Raquel Mejías-Luque, Markus Gerhard
Journal: Gut (2023)

Objective Helicobacter pylori infection is the most prevalent bacterial infection worldwide. Besides being the most important risk factor for gastric cancer development, epidemiological data show that infected individuals harbour a nearly twofold increased risk to develop colorectal cancer (CRC). However, a direct causal and functional connection between H. pylori infection and colon cancer is lacking. Design We infected two Apc -mutant mouse models and C57BL/6 mice with H. pylori and conducted a comprehensive analysis of H. pylori -induced changes in intestinal immune responses and epithelial signatures via flow cytometry, chip cytometry, immunohistochemistry and single cell RNA sequencing. Microbial signatures were characterised and evaluated in germ-free mice and via stool transfer experiments. Results H. pylori infection accelerated tumour development in Apc -mutant mice. We identified a unique H. pylori -driven immune alteration signature characterised by a reduction in regulatory T cells and pro-inflammatory T cells. Furthermore, in the intestinal and colonic epithelium, H. pylori induced pro-carcinogenic STAT3 signalling and a loss of goblet cells, changes that have been shown to contribute—in combination with pro-inflammatory and mucus degrading microbial signatures—to tumour development. Similar immune and epithelial alterations were found in human colon biopsies from H. pylori -infected patients. Housing of Apc -mutant mice under germ-free conditions ameliorated, and early antibiotic eradication of H. pylori infection normalised the tumour incidence to the level of uninfected controls. Conclusions Our studies provide evidence that H. pylori infection is a strong causal promoter of colorectal carcinogenesis. Therefore, implementation of H. pylori status into preventive measures of CRC should be considered.
Prolonged Moderate-Intensity Exercise Does Not Increase Muscle Injury Markers in Symptomatic or Asymptomatic Statin Users
Authors: Neeltje A.E. Allard, Lando Janssen, Bart Lagerwaard, Malou A.H. Nuijten, Coen C.W.G. Bongers, Richard J. Rodenburg, Paul D. Thompson, Thijs M.H. Eijsvogels, Willem J.J. Assendelft, Tom J.J. Schirris, Silvie Timmers, Maria T.E. Hopman
Journal: Journal of the American College of Cardiology (2023)
The Genetic Determinants of Aortic Distention
Authors: James P. Pirruccello, Joel T. Rämö, Seung Hoan Choi, Mark D. Chaffin, Shinwan Kany, Mahan Nekoui, Elizabeth L. Chou, Sean J. Jurgens, Samuel F. Friedman, Dejan Juric, James R. Stone, Puneet Batra, Kenney Ng, Anthony A. Philippakis, Mark E. Lindsay, Patrick T. Ellinor
Journal: Journal of the American College of Cardiology (2023)
Cancer cell genotype associated tumor immune microenvironment exhibits differential response to therapeutic STING pathway activation in high-grade serous ovarian cancer
Authors: Noor Shakfa, Deyang Li, Gwenaelle Conseil, Elizabeth D Lightbody, Juliette Wilson-Sanchez, Ali Hamade, Stephen Chenard, Natasha A. Jawa, Brian J. Laight, Afrakoma Afriyie-Asante, Kathrin Tyryshkin, Martin Koebel, Madhuri Koti
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background High-grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy characterized by resistance to chemotherapy and high rates of recurrence. HGSC tumors display a high prevalence of tumor suppressor gene loss. Given the type 1 interferon regulatory function of BRCA1 and PTEN genes and their associated contrasting T-cell infiltrated and non-infiltrated tumor immune microenvironment (TIME) states, respectively, in this study we investigated the potential of stimulator of interferon genes (STING) pathway activation in improving overall survival via enhancing chemotherapy response, specifically in tumors with PTEN deficiency. Methods Expression of PTEN protein was evaluated in tissue microarrays generated using pretreatment tumors collected from a cohort of 110 patients with HGSC. Multiplex immunofluorescence staining was performed to determine spatial profiles and density of selected lymphoid and myeloid cells. In vivo studies using the syngeneic murine HGSC cell lines, ID8- Trp53 –/– ; Pten –/– and ID8- Trp53 –/– ; Brca1 –/– , were conducted to characterize the TIME and response to carboplatin chemotherapy in combination with exogenous STING activation therapy. Results Patient tumors with absence of PTEN protein exhibited a significantly decreased disease specific survival and intraepithelial CD68+ macrophage infiltration as compared with intact PTEN expression. In vivo studies demonstrated that Pten -deficient ovarian cancer cells establish an immunosuppressed TIME characterized by increased proportions of M2-like macrophages, GR1+MDSCs in the ascites, and reduced effector CD8+ cytotoxic T-cell function compared with Brca1 -deficient cells; further, tumors from mice injected with Pten -deficient ID8 cells exhibited an aggressive behavior due to suppressive macrophage dominance in the malignant ascites. In combination with chemotherapy, exogenous STING activation resulted in longer overall survival in mice injected with Pten -deficient ID8 cells, reprogrammed intraperitoneal M2-like macrophages derived from Pten -deficient ascites to M1-like phenotype and rescued CD8+ cytotoxic T-cell activation. Conclusions This study reveals the importance of considering the influence of cancer cell intrinsic genetic alterations on the TIME for therapeutic selection. We establish the rationale for the optimal incorporation of interferon activating therapies as a novel combination strategy in PTEN-deficient HGSC.
Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging
Authors: Payel Sen, Greg Donahue, Catherine Li, Gabor Egervari, Na Yang, Yemin Lan, Neil Robertson, Parisha P. Shah, Erik Kerkhoven, David C. Schultz, Peter D. Adams, Shelley L. Berger
Journal: Nature Aging (2023)
NSD2 E1099K drives relapse in pediatric acute lymphoblastic leukemia by disrupting 3D chromatin organization
Authors: Sonali Narang, Nikki A. Evensen, Jason Saliba, Joanna Pierro, Mignon L. Loh, Patrick A. Brown, Pandurang Kolekar, Heather Mulder, Ying Shao, John Easton, Xiaotu Ma, Aristotelis Tsirigos, William L. Carroll
Journal: Genome biology (2023)

Abstract Background The NSD2 p.E1099K (EK) mutation is shown to be enriched in patients with relapsed acute lymphoblastic leukemia (ALL), indicating a role in clonal evolution and drug resistance. Results To uncover 3D chromatin architecture-related mechanisms underlying drug resistance, we perform Hi-C on three B-ALL cell lines heterozygous for NSD2 EK. The NSD2 mutation leads to widespread remodeling of the 3D genome, most dramatically in terms of compartment changes with a strong bias towards A compartment shifts. Systematic integration of the Hi-C data with previously published ATAC-seq, RNA-seq, and ChIP-seq data show an expansion in H3K36me2 and a shrinkage in H3K27me3 within A compartments as well as increased gene expression and chromatin accessibility. These results suggest that NSD2 EK plays a prominent role in chromatin decompaction through enrichment of H3K36me2. In contrast, we identify few changes in intra-topologically associating domain activity. While compartment changes vary across cell lines, a common core of decompacting loci are shared, driving the expression of genes/pathways previously implicated in drug resistance. We further perform RNA sequencing on a cohort of matched diagnosis/relapse ALL patients harboring the relapse-specific NSD2 EK mutation. Changes in patient gene expression upon relapse significantly correlate with core compartment changes, further implicating the role of NSD2 EK in genome decompaction. Conclusions In spite of cell-context-dependent changes mediated by EK, there appears to be a shared transcriptional program dependent on compartment shifts which could explain phenotypic differences across EK cell lines. This core program is an attractive target for therapeutic intervention.
The importance of reaction norms in dietary restriction and ageing research
Authors: Mirre J.P. Simons, Adam J. Dobson
Journal: Ageing Research Reviews (2023)

Ageing research has progressed rapidly through our ability to modulate the ageing process. Pharmacological and dietary treatments can increase lifespan and have been instrumental in our understanding of the mechanisms of ageing. Recently, several studies have reported genetic variance in response to these anti-ageing interventions, questioning their universal application and making a case for personalised medicine in our field. As an extension of these findings the response to dietary restriction was found to not be repeatable when the same genetic mouse lines were retested. We show here that this effect is more widespread with the response to dietary restriction also showing low repeatability across genetic lines in the fly (Drosophila melanogaster). We further argue that variation in reaction norms, the relationship between dose and response, can explain such conflicting findings in our field. We simulate genetic variance in reaction norms and show that such variation can: 1) lead to over- or under-estimation of treatment responses, 2) dampen the response measured if a genetically heterogeneous population is studied, and 3) illustrate that genotype-by-dose-by-environment interactions can lead to low repeatability of DR and potentially other anti-ageing interventions. We suggest that putting experimental biology and personalised geroscience in a reaction norm framework will aid progress in ageing research.
MyoPS: A benchmark of myocardial pathology segmentation combining three-sequence cardiac magnetic resonance images
Authors: Lei Li, Fuping Wu, Sihan Wang, Xinzhe Luo, Carlos Martín-Isla, Shuwei Zhai, Jianpeng Zhang, Yanfei Liu, Zhen Zhang, Markus J. Ankenbrand, Haochuan Jiang, Xiaoran Zhang, Linhong Wang, Tewodros Weldebirhan Arega, Elif Altunok, Zhou Zhao, Feiyan Li, Jun Ma, Xiaoping Yang, Elodie Puybareau, Ilkay Oksuz, Stephanie Bricq, Weisheng Li, Kumaradevan Punithakumar, Sotirios A. Tsaftaris, Laura M. Schreiber, Mingjing Yang, Guocai Liu, Yong Xia, Guotai Wang, Sergio Escalera, Xiahai Zhuang
Journal: Medical Image Analysis (2023)
Physical Medicine and Rehabilitation
Authors: Murray E. Brandstater
Journal: JAMA (1995)

The specialty of physical medicine and rehabilitation (physiatry) has undergone remarkable growth during the past few years. At the end of 1994, there were 4642 certified physiatrists, a 124% increase in the past 10 years. Two main factors have stimulated this growth. First, there has been an increased demand for physiatrists accompanying the expansion in the volume of rehabilitation services available for patients recovering from trauma or disabling illness. Second, the role of the physiatrist has broadened. Besides directing inpatient rehabilitation programs, many physiatrists now provide definitive care for patients with musculoskeletal or neuromuscular disorders, ie, they have broadened their participation in the physical medicine aspect of physiatry. Other physiatrists have opted to pursue subspecialty practice within physical medicine and rehabilitation, especially pediatric rehabilitation and spinal cord injury medicine. In pediatric rehabilitation, the trend has been for trainees to achieve dual-board certification in pediatrics and physical medicine and rehabilitation. For
Multisensory navigation and neuronal plasticity in desert ants
Authors: Wolfgang Rössler
Journal: Trends in Neurosciences (2023)

Cataglyphis desert ants are skilled visual navigators. Here, I present a brief overview of multisensory learning and neuronal plasticity in ants, with a particular focus on the transition from the dark nest interior to performing first foraging trips. This highlights desert ants as experimental models for studying neuronal mechanisms underlying behavioral development into successful navigators.
Exploring scenarios for the food system–zoonotic risk interface
Authors: Alon Shepon, Tong Wu, Claire Kremen, Tamar Dayan, Ivette Perfecto, Jessica Fanzo, Gidon Eshel, Christopher D Golden
Journal: The Lancet Planetary Health (2023)

The unprecedented economic and health impacts of the COVID-19 pandemic have shown the global necessity of mitigating the underlying drivers of zoonotic spillover events, which occur at the human–wildlife and domesticated animal interface. Spillover events are associated to varying degrees with high habitat fragmentation, biodiversity loss through land use change, high livestock densities, agricultural inputs, and wildlife hunting—all facets of food systems. As such, the structure and characteristics of food systems can be considered key determinants of modern pandemic risks. This means that emerging infectious diseases should be more explicitly addressed in the discourse of food systems to mitigate the likelihood and impacts of spillover events. Here, we adopt a scenario framework to highlight the many connections among food systems, zoonotic diseases, and sustainability. We identify two overarching dimensions: the extent of land use for food production and the agricultural practices employed that shape four archetypal food systems, each with a distinct risk profile with respect to zoonotic spillovers and differing dimensions of sustainability. Prophylactic measures to curb the emergence of zoonotic diseases are therefore closely linked to diets and food policies. Future research directions should explore more closely how they impact the risk of spillover events.
Long-term exposure to ambient PM2·5, active commuting, and farming activity and cardiovascular disease risk in adults in China: a prospective cohort study
Authors: Dong Sun, Cong Liu, Yinqi Ding, Canqing Yu, Yu Guo, Dianjianyi Sun, Yuanjie Pang, Pei Pei, Huaidong Du, Ling Yang, Yiping Chen, Xia Meng, Yang Liu, Jiben Liu, Rajani Sohoni, Gary Sansome, Junshi Chen, Zhengming Chen, Jun Lv, Haidong Kan, Liming Li
Journal: The Lancet Planetary Health (2023)
Real-time sewage surveillance for SARS-CoV-2 in Dhaka, Bangladesh versus clinical COVID-19 surveillance: a longitudinal environmental surveillance study (December, 2019–December, 2021)
Authors: Elizabeth T Rogawski McQuade, Isobel M Blake, Stephanie A Brennhofer, Md Ohedul Islam, Syed Shahnewaj Siraj Sony, Tonima Rahman, Md Hamim Bhuiyan, Sabrina Karim Resha, Erin G Wettstone, Lauren Hughlett, Claire Reagan, Sarah E Elwood, Yoann Mira, Ayesha S Mahmud, Kawsar Hosan, Md Raihanul Hoque, Md Masud Alam, Mahbubur Rahman, Tahmina Shirin, Rashidul Haque, Mami Taniuchi
Journal: The Lancet Microbe (2023)
Effect of nature prescriptions on cardiometabolic and mental health, and physical activity: a systematic review
Authors: Phi-Yen Nguyen, Thomas Astell-Burt, Hania Rahimi-Ardabili, Xiaoqi Feng
Journal: The Lancet Planetary Health (2023)

Nature prescriptions are gaining popularity as a form of social prescribing in support of sustainable health care. This systematic review and meta-analysis aims to synthesise evidence on the effectiveness of nature prescriptions and determine the factors important for their success. We searched five databases from inception up to July 25, 2021. Randomised and non-randomised controlled studies featuring a nature prescription (ie, a referral or an organised programme, by a health or social professional, to encourage spending time in nature) were included. Two reviewers independently conducted all steps of study selection; one reviewer collected summary data from published reports and conducted the risk of bias assessment. Random-effect DerSimonian-Laird meta-analyses were conducted for five key outcomes. We identified 92 unique studies (122 reports), of which 28 studies contributed data to meta-analyses. Compared with control conditions, nature prescription programmes resulted in a greater reduction in systolic blood pressure (mean difference -4·82 mm Hg [-8·92 to -0·72]) and diastolic blood pressure (mean difference -3·82 mm Hg [-6·47 to -1·16). Nature prescriptions also had a moderate to large effect on depression scores (post-intervention standardised mean difference -0·50 [-0·84 to -0·16]; change from baseline standardised mean difference -0·42 [-0·82 to -0·03]) and anxiety scores (post-intervention standardised mean difference -0·57 [-1·12 to -0·03]; change from baseline standardised mean difference -1·27 [-2·20 to -0·33]). Nature prescriptions resulted in a greater increase in daily step counts than control conditions (mean difference 900 steps [790 to 1010]) but did not improve weekly time of moderate physical activity (mean difference 25·90 min [-10·26 to 62·06]). A subgroup analysis restricted to studies featuring a referring institution showed stronger effects on depression scores, daily step counts, and weekly time of moderate physical activity than the general analysis. Beneficial effects on anxiety and depression scores were mainly provided by interventions involving social professionals whereas beneficial effects on blood pressures and daily step counts were provided mainly by interventions involving health professionals. Most studies have a moderate to high risk of bias. Nature prescription programmes showed evidence of cardiometabolic and mental health benefits and increases in walking. Effective nature prescription programmes can involve a range of natural settings and activities and can be implemented via social and community channels, in addition to health professionals.
Epsin1-mediated exosomal sorting of Dll4 modulates the tubular-macrophage crosstalk in diabetic nephropathy
Authors: Jia-Lu Liu, Lei Zhang, Ying Huang, Xiao-Hui Li, Yi-Fei Liu, Shu-Min Zhang, Yue-E Zhao, Xiao-Jun Chen, Yu Liu, Li-Yu He, Zheng Dong, Fu-You Liu, Lin Sun, Li Xiao
Journal: Molecular Therapy (2023)

Tubular epithelial cells (TECs) play critical roles in the development of diabetic nephropathy (DN), and can activate macrophages through the secretion of exosomes. However, the mechanism(s) of TEC-exosomes in macrophage activation under DN remains unknown. By mass spectrometry, 1,644 differentially expressed proteins, especially Dll4, were detected in the urine exosomes of DN patients compared with controls, which was confirmed by western blot assay. Elevated Epsin1 and Dll4/N1ICD expression was observed in kidney tissues in both DN patients and db/db mice and was positively associated with tubulointerstitial damage. Exosomes from high glucose (HG)-treated tubular cells (HK-2) with Epsin1 knockdown (KD) ameliorated macrophage activation, TNF-α, and IL-6 expression, and tubulointerstitial damage in C57BL/6 mice in vivo. In an in vitro study, enriched Dll4 was confirmed in HK-2 cells stimulated with HG, which was captured by THP-1 cells and promoted M1 macrophage activation. In addition, Epsin1 modulated the content of Dll4 in TEC-exosomes stimulated with HG. TEC-exosomes with Epsin1-KD significantly inhibited N1ICD activation and iNOS expression in THP-1 cells compared with incubation with HG alone. These findings suggested that Epsin1 could modulate tubular-macrophage crosstalk in DN by mediating exosomal sorting of Dll4 and Notch1 activation.
Access to essential cancer medicines for children: a comparative mixed-methods analysis of availability, price, and health-system determinants in east Africa
Authors: Kadia Petricca, Joyce Kambugu, Jessie Githang'a, William M Macharia, Festus Njuguna, Angela McLigeyo, Mary Nyangasi, Jackson Orem, Aimable Kanyamuhunga, Rehema Laiti, Deogratias Katabalo, Kristin Schroeder, Khama Rogo, Bryan Maguire, Lucy Wambui, Jean N Nkurunziza, Bryan Wong, Joshua Neposlan, Lilian Kilawe, Sumit Gupta, Avram E Denburg
Journal: The Lancet Oncology (2023)